Hyperferritinaemia without iron overload in a blood donor.

Abstract

Dear Sir, High levels of ferritinaemia are commonly found in the clinical practice, both in acquired conditions (chronic inflammation, liver diseases, chronic anaemia caused by ineffective erythropoiesis and/or by transfusion, neoplasias, collagen diseases) and genetic disorders (haemochromatosis types 1–4, hereditary hyperferritinaemia cataract syndrome - HHCS)1,2, and may or may not be associated with iron overload (parenchymal or reticuloendothelial). For this reason, a full evaluation of a patient with hyperferritinaemia requires a personal and family history, biochemical tests, genetic tests and measurements of tissue iron3. Here we present the clinical case of “unusual” hyperferritinaemia in a blood donor. The subject, a male born in 1968, started making blood donations in 2005 in a different blood bank. In October 2005 his ferritin level was found to be 1,288 ng/mL. In February 2006 the ferritin level was 1,321 ng/ml, blood iron 81 mg/dL, transferrin 256 mg/dL, saturation index 22%, haemoglobin 15.8 g/dL, mean corpuscular volume 85.66 fL; liver function tests were normal, hepatic virology was negative and his blood glucose was 86 mg/dL. As regards HFE genotype, the patient was heterozygosis for H63D, with normal TFR2 and normal FPN1. The subject started regular phlebotomy twice monthly; he was diagnosed with haemochromatosis and advised to continue with the phlebotomies, which he did so for 3 years. The patient came to our blood bank in November 2008 when his ferritin was 1,909 ng/mL, blood iron 32 mg/dL, transferrin 393 mg/dL, saturation index 6%, haemoglobin 12.5 g/dL, mean corpuscular volume 69 fL, and C-reactive protein 0.24. His past clinical history included an operation for bilateral cataracts in 2001 (when he was 31 years old). After interruption of the phlebotomies, the subject underwent magnetic biosusceptometry with a superconducting quantum interference device (SQUID) in S. Luigi Hospital, Orbassano, Italy. His hepatic iron was 175 (normal value 0-400) and his total body iron was 10.8 mg/Kg/body weight. The analysis of the genetic sequences of the ferritin promoter L showed a mutated phenotype (U46G mutation in heterozygosis)4. The genotype is compatible with HHCS. The diagnosis of HHCS was strongly suggested by the hyperferritinaemia with normal transferrin saturation, the absence of inflammatory, hepatic, neoplastic, or haematological diseases, the HFE genotype not at risk (heterozygosis for H63D), the absence of mutations in the TFR2 and FPN1 genes, the SQUID results (normal hepatic iron and reduced total body iron) and the clinical history (bilateral cataracts in a young subject); the diagnosis was confirmed by genetic analysis. HHCS is a form of hereditary hyperferritinaemia, not associated with iron overload, with an autosomal dominant transmission. It is caused by a mutation of the gene codifying for the synthesis of the L (light) chains of ferritin; such a mutation makes ferritin production independent of cellular iron content, so that ferritin is produced in excess. Iron-free ferritin shells are deposited in tissues; these shells cannot be removed. These deposits do not cause any damage to tissues, except for the lens, which they render progressively opaque with the development of cataracts. Cataract surgery solves this problem5. It is important to recognise this situation in order to avoid further research and to distinguish it from others in which the hyperferritinaemia is a sign of iron overload or of an inflammatory or malignant disease. Assaying the ferritin levels in other family members can lead to the identification of the subjects who are at risk of developing the ocular pathology. The genetic tests we performed on the subject’s children did not reveal any mutations and their level of ferritin was normal. Had the correct diagnosis been made earlier, our subject would have avoided the intensive phlebotomy regime that he underwent. The regular removal of blood led to the development of iron depletion and iron-deficiency anaemia without correcting the hyperferritinaemia.